Sofie E Jørgensen1,2, Ali Al-Mousawi1,2, Kristian Assing3, Ulla Hartling4, Dorthe Grosen4, Niels Fisker4, Christian Nielsen3, Marianne A Jakobsen3, Trine H Mogensen5,6,7. 1. Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark. 2. Department of Biomedicine, Aarhus University, Aarhus, Denmark. 3. Department of Clinical Immunology, Odense University Hospital, Odense, Denmark. 4. Department of Pediatrics, Odense University Hospital, Odense, Denmark. 5. Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark. trine.mogensen@biomed.au.dk. 6. Department of Biomedicine, Aarhus University, Aarhus, Denmark. trine.mogensen@biomed.au.dk. 7. Department of Clinical Medicine, Aarhus University, Aarhus, Denmark. trine.mogensen@biomed.au.dk.
Abstract
BACKGROUND: STK4 deficiency due to homozygous mutations in the STK4 gene encoding the STK4/MST1 kinase was first described in 2012. STK4/MST1 kinase regulates cell proliferation, survival, differentiation, and immune responses through canonical and non-canonical Hippo signaling pathways. OBJECTIVE: We describe an 11-year-old girl with a clinical presentation consisting of severe recurrent herpes zoster, chronic warts, and recurrent pneumonias, as well as a somatic phenotype with hypothyroidism and low stature. Whole exome sequencing revealed STK4 deficiency due to homozygosity for a novel frameshift variant in STK4, c.523dupA, p.(L174fsTer45), resulting in a premature stop codon within the kinase domain. METHODS: We performed a thorough investigation of the genetics and innate and adaptive immunological abnormalities in STK4 deficiency. RESULTS: We show significantly impaired type I, II, and III interferon (IFN) responses and partly reduced proinflammatory cytokine responses to ligands of Toll-like receptor (TLR)3, TLR9, and the cytosolic RNA and DNA sensors as well as to microorganisms. Impaired IFN responses could be attributed to reduced phosphorylation of TBK1 and IRF3. Moreover, virus infection induced enhanced cell death by apoptosis. Importantly, autophagy pathways were slightly disturbed, with enhanced LC3B-Ito LCB3-II conversion at the single cell level but normal overall formation of LCB3 punctae. Finally, the patient displayed some indicators of impaired adaptive immunity in the form of insufficient vaccination responses, T cell lymphopenia, and reduced Treg fractions, although with largely normal T cell proliferation and normal IFNg production. CONCLUSION: Here, we demonstrate disturbances in various immune cell populations and pathways involved in innate immune responses, cell death, autophagy, and adaptive immunity in a patient homozygous for a novel STK4 frameshift mutation.
BACKGROUND: STK4 deficiency due to homozygous mutations in the STK4 gene encoding the STK4/MST1 kinase was first described in 2012. STK4/MST1 kinase regulates cell proliferation, survival, differentiation, and immune responses through canonical and non-canonical Hippo signaling pathways. OBJECTIVE: We describe an 11-year-old girl with a clinical presentation consisting of severe recurrent herpes zoster, chronic warts, and recurrent pneumonias, as well as a somatic phenotype with hypothyroidism and low stature. Whole exome sequencing revealed STK4 deficiency due to homozygosity for a novel frameshift variant in STK4, c.523dupA, p.(L174fsTer45), resulting in a premature stop codon within the kinase domain. METHODS: We performed a thorough investigation of the genetics and innate and adaptive immunological abnormalities in STK4 deficiency. RESULTS: We show significantly impaired type I, II, and III interferon (IFN) responses and partly reduced proinflammatory cytokine responses to ligands of Toll-like receptor (TLR)3, TLR9, and the cytosolic RNA and DNA sensors as well as to microorganisms. Impaired IFN responses could be attributed to reduced phosphorylation of TBK1 and IRF3. Moreover, virus infection induced enhanced cell death by apoptosis. Importantly, autophagy pathways were slightly disturbed, with enhanced LC3B-Ito LCB3-II conversion at the single cell level but normal overall formation of LCB3 punctae. Finally, the patient displayed some indicators of impaired adaptive immunity in the form of insufficient vaccination responses, T cell lymphopenia, and reduced Treg fractions, although with largely normal T cell proliferation and normal IFNg production. CONCLUSION: Here, we demonstrate disturbances in various immune cell populations and pathways involved in innate immune responses, cell death, autophagy, and adaptive immunity in a patient homozygous for a novel STK4 frameshift mutation.